Arrestins in the Cardiovascular System - Progress in Molecular Biology and Translational Science - page 311

mediate downstream signaling of non-7TMRs, for example, the insulin-like
growth factor-1 receptor and transforming growth factor beta receptor type
III. 106 However, all the cardiovascular-related actions of b arrs on non-
GPCRs reported to date pertain to EGFR transactivation. Thus, the
VSM cell AT 1 R, the cardiomyocyte b ARs, and the cardiac urotensin II
receptor (also a GPCR) have all been reported to induce EGFR trans-
activation and subsequent ERK1/2 activation via b arrs, which may contrib-
ute to VSM or cardiac hypertrophy. 36,107-109
The precise molecular pathways underlying this type of cardiovascular
b arr-dependent signaling have not been fully elucidated and may vary for
each GPCR. Cardiac AT 1 R-stimulated b arr-dependent EGFR trans-
activation opposes chronic catecholaminergic stimulation-induced dilated
cardiomyopathy and cardiac apoptosis in a mouse model of HF, since mice
incapable of transactivating cardiac EGFR displayed significantly less cardiac
hypertrophy and improved survival compared to wild-type mice. 25 The
mechanism probably involves transactivated EGFR-induced ERK1/2 acti-
vation. 109,110 Similarly, urotensin II receptor-mediated EGFR trans-
activation has been shown to be b arr-dependent and to reduce cardiac
apoptosis in mice with chronic pressure overload compared to mice in
which cardiac EGFR was blocked. 107
However, the involvement of b arrs in cardiac GPCR-mediated EGFR
transactivation, cardiomyocyte proliferation, and survival appears to be case-
and GPCR-specific. AT 1 R-stimulated EGFR transactivation and hypertro-
phy are totally dependent on G q/11 proteins, and not at all on b arrs, in
neonatal rat ventricular cardiomyocytes. 111 Conversely, ligand-independent,
mechanical stretch-stimulated AT 1 R-mediated EGFR transactivation in the
heart, which increases survival by promoting Akt/PKB activation and lower-
ing cardiac apoptosis, is b arr2-dependent ( Table 12.1 ). 34 In VSM cells, AT 1 R
transactivates the EGFR via b arr2 ( Table 12.1 ) leading to ERK1/2 activation
and increased VSM cell DNA synthesis. 36 Of note, there is significant cross-
talk between AT 1 Rand b AR signaling on cardiomyocyte contractility and
ERK1/2 activation, 112,113 which is subject to regulation by b arrs. This could
represent another mechanism by which cardiac b arrs, acting as transducers of
signals from one receptor to another (either a GPCR or a non-GPCR), affect
cardiac hypertrophy and survival/apoptosis. To sum up, cardiac EGFR trans-
activation by GPCRs, which enhances both survival and hypertrophy, can
proceed either through b arrs (mainly b arr2) or through G proteins, depending
on the GPCR, ligand and cellular/tissue model studied. In any case, trans-
activation of this non-GPCR appears to be an important signaling mechanism